People make terrible jokes about “mad cow” disease. (“Why is PMS called PMS? Because mad cow was already taken.”) Pundits use it as an example of an over-hyped disease (and to be fair, estimates of total cases due to the consumption of contaminated beef in the UK have varied widely, ranging from a few thousand up to well over 100,000). Vegetarians note it as one benefit that comes from their soyburgers. Everyone, it seems, has an opinion.

So-called “mad cow” disease, in humans, is a progressive neurological disorder more correctly called variant Creuzfield-Jacob disease (vCJD). This is due to infection with an agent called a prion. Additional background can be found here, but briefly, the prion is actually a misfolded form of a normal host protein (called PrPc, standing for “prion protein, cellular form”). Its a concern to human health largely because the disease swept through cattle herds in the UK in the 1980s, and it is uncertain just how many humans unknowingly consumed contaminated beef–and therefore, how many may eventually develop vCJD.

vCJD is one of a family of transmissible spongiform encephalopathies (TSEs); others in this family include scrapie (which affects sheep), chronic wasting disease (which affects deer, elk, and moose, among others), and another human TSE called kuru (discussed further below).
Kuru was first recognized a half-century ago among the Fore group in the highlands of Papua New Guinea. Investigations showed that the disease was spread by cannibalism (though, at the time, the causative prion had not yet been identified). Women and children became infected during ritual consumption of the bodies of deceased relatives. Men did not participate in this, and were largely spared from development of kuru. This practice was outlawed in 1954, and ceased by 1960. Around this time, extensive surveillance for kuru in this area was instituted, initially identifying a relatively large number of cases (approximately 200 deaths per year in the late 1950s). And while incident disease cases dropped dramatically over the decades (the average incubation period was found to be ~12 years, similar to one form of vCJD), surveillance has continued.

A new Lancet paper reports on recent results of this surveillance, detailing cases of kuru diagnosed over the last decade–at least 36 years removed from the end of cannibalism in this group, and likely over 50 years from the time of exposure. From 1996 to 2004, 11 cases were identified.

The kuru cases they found during this period were unique for several reasons. First and most striking, because most of them were in men. As I mentioned earlier, men make up a small percentage of kuru cases–of the 2700 total cases diagnosed during the course of the epidemic, only ~2% were in men (versus 64% in this study). This is likely because their only exposure comes during childhood, when they participated in the ritual feasting, while women were exposed throughout their lives. After about the age of 6, boys were taken from their mothers and brought up in the mens’ house, where, the paper notes, “they participated little in feasts and did not eat the brain, by far the most infectious organ in kuru.” The male cases in this study ranged in age from 46 to 63 years old, suggesting an incubation period of over 50 years if most of their exposure occurred before the age of 6.

DNA was available for 10 of these cases. A genetic analysis of the several loci was undertaken, as genetic susceptibility to prion disease has been documented both in humans (in the case of vCJD) and in animals (to various TSEs). In humans, for example, a polymorphism in PrPc appears to increase susceptibility to both the acquired CJD as well as what’s known as “sporadic” CJD (in which the prion is not acquired exogenously). People who carry two copies of this particular allele (with a methionine at codon 129 of the PrPc gene rather than a valine) represent about 38% of the European population, but thus far, have accounted for almost all clinical CJD cases. When this gene was examined in those 10 fatal kuru cases, 8 were found to be heterozygotes, with one each homozygous for valine and methionine at codon 129.

What this suggests is that, perhaps, those with a particular genetic makeup (such as those homozygous for the methionine129 allele) may be the most susceptible to TSEs, making them the first wave of TSE cases in an epidemic. Therefore, what we are seeing now in the UK and elsewhere in Europe may be just the beginning of the epidemic; heterozygotes (like those in the current study) may have a longer incubation period for the disease. The authors suggest that:

Mean incubation periods of human BSE [bovine spongioform encephalopathy] infection of 30 years or more should therefore be regarded as possible, if not probable, with the longest incubation periods approaching (and perhaps exceeding) the typical human lifespan.

This conclusion is reached by extrapolating from kuru to human exposure to BSE, but it should be noted that there are some problems with this. First, kuru represents a human-to-human transmission event (dubbed “intraspecies recycling” in the paper). Studies of prions in a laboratory setting using animal models have shown that there is a species barrier to transmission, and that prions that have been adapted to a particular species–for example, prions that have been passaged once in a mouse, and are then harvested and inoculated into a second mouse–result in a decreased incubation period and a higher lethality when compared to the primary passage (which would have come from another animal species, such as a cow or human). Therefore, kuru may have a shorter incubation period and higher virulence than BSE transmitted to humans. Additionally, the concentration of prions varies by animal tissue. Kuru has been especially associated with handling or consumption of the host brain (high in prion concentration), whereas individuals exposed to BSE have been so via contaminated animal muscle (theoretically, with minimal nervous tissue involvement). Therefore, the infectious dose of the prion should be much lower for BSE than that in kuru, which may either extend the incubation period beyond even 30 years, or may mean that the theoretical “mad cow” epidemic will never materialize. Unfortunately, only time will tell.

Comments

It’s interesting, actually, how weak the evidence for cannibalism spreading the disease actually is. An alternative explanation is that people were infected through skin cuts during the funerary rites, and in fact at least with non-human primates kuru is far more infectious by injection than by the oral route. Gajdusek originally considered this possibility:

Natural transmission is believed to be related to the mourning rituals of the Fore people, which consisted of cannibalistic consumption of their dead relatives. Women and children who were engaged in the preparation of food could have becomes infected by selfinoculation through abrasions or cuts, or from nasal or conjunctival inoculation. In contrast to men, they also consumed the less well-cooked offal, including the brain; this could further account for the striking predominance of afflicted women and children of both sexes.

If you go way back and read the original papers on kuru by Gajdusek, there seems to be little if any actual evidence linking kuru to cannibalism — in fact, in one of his earliest papers on the disease he explicitly rejects cannibalism as having a link, and lists a number of epidemiological and demographic reasons why:

There was no item of the Fore diet not also consumed in similar quantities by some neighboring kuru-free groups. Cannibalism, which included principally the consumption of kinsmen who had died of various causes, including kuru, by their close relatives, however, was more specifically a Fore trait than one of many of their neighbors. Early in the kuru investigation the possibility that cannibalism was involved in some hypersensitization or latent virus transmission was considered. However, neighbors such as the Tudahwe and Daribi near Kareimui and many other groups in New Guinea were likewise cannibal without suffering from kuru, and many of the younger kuru victims after 1958 were though never to have eaten dead relatives.

Later, though, he switches to taking the cannibalism theory as a given, even though to the best of my knowledge no new data became available in the interim.

A third-party article (John D Matthews, Robert Glasse, and Shirley Lindenbaum. Kuru and Cannibalism. Lancet 2:449-452 (1968)) listed some reasons to suspect canniablism, and that’s the only one I found that may have swayed Gajdusek — but it’s strange that some of the links those people claim as evidence, had been specifically raised and refuted in his earlier list.

One of the arguments that’s supposed to have been proof that cannibalism caused kuru is that kuru was eliminated when cannibalism stopped — but of course now that new kuru cases are turning up, that’s not applicable.

I don’t know that this changes the interpretation of the nvCJD risk particularly, but I jsut thought I’d throw it out.

You bring up a lot of interesting points. I’ve also read a bit of the literature regarding the importance (or lack thereof) of cannibalism in transmission, but they’ve been mainly summaries and reviews of the lit, so I’m not nearly as familiar with the original papers. A few notes, though.

Early in the kuru investigation the possibility that cannibalism was involved in some hypersensitization or latent virus transmission was considered. However, neighbors such as the Tudahwe and Daribi near Kareimui and many other groups in New Guinea were likewise cannibal without suffering from kuru…

This is pretty easily explained by noting that the misfolded protein simply may not have originated in any of the neighbors. Even in the Fore, it only would have had to originated once (and now that I think about it, I’m not sure if there’s been any investigations into the source of the epidemic–did the prion originally come from another animal species that they ate? Was it a spontaneous case in a human, that was then passed along via funerary rites–either via cutting, or cannibalism? Anyhoo…) and then been passed among relatives and other mourners. As long as other neighboring tribes weren’t involved in these rituals (even if they had their own), they could easily have stayed uninfected.

and many of the younger kuru victims after 1958 were though never to have eaten dead relatives.

I don’t know enough about the research done to conclude these victims didn’t partake of the feasts to really elaborate on this, but it’s certainly possible that cannibalism isn’t the only way this was spread. We know that in other prion diseases, prions can exist in milk and urine, and are very stable in the environment. It seems likely that consumption or accidental inoculation via preparation would provide the highest doses, but that doesn’t mean other routes weren’t involved as well. That also goes to your comment about skin cuts (which the authors do mention alongside cannibalism, though they don’t focus on cuts).

One of the arguments that’s supposed to have been proof that cannibalism caused kuru is that kuru was eliminated when cannibalism stopped — but of course now that new kuru cases are turning up, that’s not applicable.

Well, not quite. Even in this new paper, there weren’t any cases in people who were born after cannibalism was outlawed; years of birth range from 1933 to 1949, so they would have had plenty of time to be exposed before the government cracked down on it. Had there been new cases in people born after 1960, that would be more difficult to account for, but none have been found (to my knowledge, anyway).

To BMurray: Prions are indeed fascinating and unique “entities” (“organisms” certainly wouldn’t be appropriate), but I don’t think they can be precisely described as “self-replicating.” Since they simply impose their conformation on another preexisting protein of the same or similar sequence, rather than induce the de novo synthesis of a new protein, I don’t think they really “self-replicate” in the way that the first hypothetical protein/ribozyme would presumably have.

Re the main article: I don’t have access to the article itself, or most medical research at all at the moment, but I’m curious if the nvCJD incidence in Europe is rising or falling right now. From what I recall in the news, it was still rising in the late 1990s. They seem to be in the midst of the homozygote-portion of the epidemic right now, and the present trend should give us a hint at what part of the incidence over time curve we presently sit. From the kuru data, we would also anticipate a boomlet far into the future of heterozygotes, but it should be very much smaller and more diffuse than the homozygote boom, if it manifests at all.

TSEs have been rampant in the USA for decades in many
species, and they all have been rendered and fed back
to animals for human/animal consumption. I propose that
the current diagnostic criteria for human TSEs only
enhances and helps the spreading of human TSE from the
continued belief of the UKBSEnvCJD only theory in 2005.
With all the science to date refuting it, to continue
to validate this myth, will only spread this TSE agent
through a multitude of potential routes and sources
i.e. consumption, surgical, blood, medical, cosmetics
etc. I propose as with Aguzzi, Asante, Collinge,
Caughey, Deslys, Dormont, Gibbs, Ironside, Manuelidis,
Marsh, et al and many more, that the world of TSE
Tranmissible Spongiform Encephalopathy is far from an
exact science, but there is enough proven science to
date that this myth should be put to rest once and for
all, and that we move forward with a new classification
for human and animal TSE that would properly identify
the infected species, the source species, and then the
route. This would further have to be broken down to
strain of species and then the route of transmission
would further have to be broken down. Accumulation and
Transmission are key to the threshold from subclinical
to clinical disease. To continue with this myth that the U.K. strain of
BSE one strain in cows, and the nv/v CJD, one strain in
humans, and that all the rest of human TSE is one
single strain i.e. sporadic CJD (when to date there are
6 different phenotypes of sCJD), and that no other
animal TSE transmits to humans, to continue with this
masquerade will only continue to spread, expose, and
kill, who knows how many more in the years and decades
to come. ONE was enough for me, My Mom, hvCJD, DOD
12/14/97 confirmed, which is nothing more than another
mans name added to CJD, like CJD itself, Jakob and
Creutzfeldt, or Gerstmann-Straussler-Scheinker
syndrome, just another CJD or human TSE, named after
another human. WE are only kidding ourselves with the
current diagnostic criteria for human and animal TSE,
especially differentiating between the nvCJD vs the
sporadic CJD strains and then the GSS strains and also
the FFI fatal familial insomnia strains or the ones
that mimics one or the other of those TSE? Tissue
infectivity and strain typing of the many variants of
the human and animal TSEs are paramount in all variants
of all TSE. There must be a proper classification that
will differentiate between all these human TSE in order
to do this. With the CDI and other more sensitive
testing coming about, I only hope that my proposal will
some day be taken seriously.

My name is Terry S. Singeltary Sr. and I am no
scientist, no doctor and have no PhDs, but have been
independently researching human and animal TSEs since
the death of my Mother to the Heidenhain Variant of
Creutzfeldt Jakob Disease on December 14, 1997
‘confirmed’. …TSS

IF we all believe the BSe that the USDA is trying to put out now about atypical BSE in USA cattle just arising spontaneously,
then we all should believe in the tooth fairy and santa claus as well.

IF USA scrapie transmitted to USA cattle long ago in experiments in a lab in Mission Texas did not produce UK BSE,
but something very different, then why would USA TSE cattle produce the UK human version of mad cow i.e. nvCJD?
IT wouldn’t. USA sporadic cjd is increasing, the USA also has atypical human cases of unknown origin as well?

THERE are over 20 strains of scrapie, plus the atypical in sheep, and these strains are increasing in numbers.

SCRAPIE, CWD, AND TSE IN CATTLE i.e. ANIMAL TSE RAMPANT IN USA FOR DECADES, and amplified via rendering and
feeding practices, where USDA triple firewalls against BSE were nothing more than a mere smoke screen.

NO test tube TSE by either Prusiner or Soto, to date, have ever produced a TSE identical to the sporadic CJD. IN fact,
no test tube TSE has ever been produced that resembles _any_ natural field TSE.

IF you feed BSE tainted materials to cattle and primate, you have BSE and nvCJD.
IF you feed USA sheep strain to USA cattle, you get USA TSE.
IF you feed USA tainted cattle to humans, you get USA mad cow disease.
IF you feed sporadic CJD to primate you get a CJD infected primate.
NOTHING spontaneous about it at all.

USA is in a very unique situation. there are more documented TSE in different species than any other country,
all of which have been rendered and fed back to animals for human and animal consumption, for decades. Millions exposed,
and of these Millions, how many surgical and dental procedures have been done on these exposed, to pass on to others,
via the ‘friendly fire’ mode of transmission?

IF, the spontaneous TSE was true, then this would be Prusiner and everyone else that is trying to cash in on this agent with
there TSE rapid test, this would be there dream come true. IT would require mandatory BSE/TSE testing of all species,
due to the fact you could not ever eradicate it through any intervention. BUT, then again, the spontaneous TSE is like believing
in the tooth fairy or santa claus will be arriving at your house this year.

Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved December 23, 2003 (received for review September 9, 2003)

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are mammalian neurodegenerative disorders characterized by a posttranslational conversion and brain accumulation of an insoluble, protease-resistant isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). Human and animal TSE agents exist as different phenotypes that can be biochemically differentiated on the basis of the molecular mass of the protease-resistant PrPSc fragments and the degree of glycosylation. Epidemiological, molecular, and transmission studies strongly suggest that the single strain of agent responsible for bovine spongiform encephalopathy (BSE) has infected humans, causing variant Creutzfeldt-Jakob disease. The unprecedented biological properties of the BSE agent, which circumvents the so-called “species barrier” between cattle and humans and adapts to different mammalian species, has raised considerable concern for human health. To date, it is unknown whether more than one strain might be responsible for cattle TSE or whether the BSE agent undergoes phenotypic variation after natural transmission. Here we provide evidence of a second cattle TSE. The disorder was pathologically characterized by the presence of PrP-immunopositive amyloid plaques, as opposed to the lack of amyloid deposition in typical BSE cases, and by a different pattern of regional distribution and topology of brain PrPSc accumulation. In addition, Western blot analysis showed a PrPSc type with predominance of the low molecular mass glycoform and a protease-resistant fragment of lower molecular mass than BSE-PrPSc. Strikingly, the molecular signature of this previously undescribed bovine PrPSc was similar to that encountered in a distinct subtype of sporadic Creutzfeldt-Jakob disease.

Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.

Between FYs 2002 and 2004, FSIS condemned 680 cattle of all ages due to CNS symptoms. About 357 of these could be classified as adult. We could validate that ONLY 162 were tested for BSE (per APHIS records. …

snip…

WE interviewed officials at five laboratories that test for rabies. Those officials CONFIRMED THEY ARE NOT REQUIRED TO SUBMIT RABIES-NEGATIVE SAMPLES TO APHIS FOR BSE TESTING. A South Dakota laboratory official said they were not aware they could submit rabies-negative samples to APHIS for BSE testing. A laboratory official in another State said all rabies-negative cases were not submitted to APHIS because BSE was ”NOT ON THEIR RADAR SCREEN.” Officials from New York, Wisconsin, TEXAS, and Iowa advised they would NOT submit samples from animals they consider too young. Four of the five States contacted defined this age as 24 months; Wisconsin defined it as 30 months. TEXAS officials also advised that they do not always have sufficient tissue remaining to submit a BSE sample. …

Bovine Spongiform Encephalopathy (BSE) is a prion
disease of cattle. Since 1986, when BSE was recognized,
over 180,000 cattle in the UK have developed the
disease, and approximately one to three million are
likely to have been infected with the BSE agent, most
of which were slaughtered for human consumption before
developing signs of the disease. The origin of the
first case of BSE is unknown, but the epidemic was
caused by the recycling of processed waste parts of
cattle, some of which were infected with the BSE agent
and given to other cattle in feed. Control measures
have resulted in the consistent decline of the epidemic
in the UK since 1992. Infected cattle and feed exported
from the UK have resulted in smaller epidemics in other
European countries, where control measures were applied
later.

Compelling evidence indicates that BSE can be
transmitted to humans through the consumption of prion
contaminated meat. BSE-infected individuals eventually
develop vCJD with an incubation time believed to be on
average 10 years. As of November 2004, three cases of
BSE have been reported in North America. One had been
imported to Canada from the UK, one was grown in
Canada, and one discovered in the USA but of Canadian
origin. There has been only one case of vCJD reported
in the USA, but the patient most likely acquired the
disease in the United Kingdom. If current control
measures intended to protect public and animal health
are well enforced, the cattle epidemic should be
largely under control and any remaining risk to humans
through beef consumption should be very small. (For
more details see Smith et al. British Medical Bulletin,
66: 185. 2003.)

Chronic Wasting Disease (CWD) is a prion disease of elk
and deer, both free range and in captivity. CWD is
endemic in areas of Colorado, Wyoming, and Nebraska,
but new foci of this disease have been detected in
Nebraska, South Dakota, New Mexico, Wisconsin,
Mississippi Kansas, Oklahoma, Minnesota, Montana, and
Canada. Since there are an estimated 22 million elk and
deer in the USA and a large number of hunters who
consume elk and deer meat, there is the possibility
that CWD can be transmitted from elk and deer to
humans. As of November 2004, the NPDPSC has examined 26
hunters with a suspected prion disease. However, all of
them appeared to have either typical sporadic or
familial forms of the disease. The NPDPSC coordinates
with the Centers for Disease Control and state health
departments to monitor cases from CWD-endemic areas.
Furthermore, it is doing experimental research on CWD
transmissibility using animal models. (For details see
Sigurdson et al. British Medical Bulletin. 66: 199.
2003 and Belay et al. Emerging Infectious Diseases.
10(6): 977. 2004.)

SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM
1997 TO 2004. SPORADIC CJD CASES TRIPLED, and that is
with a human TSE surveillance system that is terrible
flawed. in 1997 cases of the _reported_ cases of cjd
were at 54, to 163 _reported_ cases in 2004. see stats
here;

Objective:
The objective of this cooperative research project with Dr. Maria Caramelli
from the Italian BSE Reference Laboratory in Turin, Italy, is to conduct
comparative studies with the U.S. bovine spongiform encephalopathy (BSE)
isolate and the atypical BSE isolates identified in Italy. The studies will
cover the following areas: 1. Evaluation of present diagnostics tools used
in the U.S. for the detection of atypical BSE cases. 2. Molecular comparison
of the U.S. BSE isolate and other typical BSE isolates with atypical BSE
cases. 3. Studies on transmissibility and tissue distribution of atypical
BSE isolates in cattle and other species.

Approach:
This project will be done as a Specific Cooperative Agreement with the
Italian BSE Reference Laboratory, Istituto Zooprofilattico Sperimentale del
Piemonte, in Turin, Italy. It is essential for the U.S. BSE surveillance
program to analyze the effectiveness of the U.S diagnostic tools for
detection of atypical cases of BSE. Molecular comparisons of the U.S. BSE
isolate with atypical BSE isolates will provide further characterization of
the U.S. BSE isolate. Transmission studies are already underway using brain
homogenates from atypical BSE cases into mice, cattle and sheep. It will be
critical to see whether the atypical BSE isolates behave similarly to
typical BSE isolates in terms of transmissibility and disease pathogenesis.
If transmission occurs, tissue distribution comparisons will be made between
cattle infected with the atypical BSE isolate and the U.S. BSE isolate.
Differences in tissue distribution could require new regulations regarding
specific risk material (SRM) removal.

3.57 The experiment which might have determined whether BSE and scrapie were
caused by the same agent (ie, the feeding of natural scrapie to cattle) was
never undertaken in the UK. It was, however, performed in the USA in 1979,
when it was shown that cattle inoculated with the scrapie agent endemic in
the flock of Suffolk sheep at the United States Department of Agriculture in
Mission, Texas, developed a TSE quite unlike BSE. 32 The findings of the
initial transmission, though not of the clinical or neurohistological
examination, were communicated in October 1988 to Dr Watson, Director of the
CVL, following a visit by Dr Wrathall, one of the project leaders in the
Pathology Department of the CVL, to the United States Department of
Agriculture. 33 The results were not published at this point, since the
attempted transmission to mice from the experimental cow brain had been
inconclusive. The results of the clinical and histological differences
between scrapie-affected sheep and cattle were published in 1995. Similar
studies in which cattle were inoculated intracerebrally with scrapie inocula
derived from a number of scrapie-affected sheep of different breeds and from
different States, were carried out at the US National Animal Disease Centre.
34 The results, published in 1994, showed that this source of scrapie agent,
though pathogenic for cattle, did not produce the same clinical signs of
brain lesions characteristic of BSE.

The findings of the initial transmission, though not of the clinical or
neurohistological examination, were communicated in October 1988 to Dr
Watson, Director of the CVL, following a visit by Dr Wrathall, one of the
project leaders in the Pathology Department of the CVL, to the United States
Department of Agriculture. 33

The results were not published at this point, since the attempted
transmission to mice from the experimental cow brain had been inconclusive.
The results of the clinical and histological differences between
scrapie-affected sheep and cattle were published in 1995. Similar studies in
which cattle were inoculated intracerebrally with scrapie inocula derived
from a number of scrapie-affected sheep of different breeds and from
different States, were carried out at the US National Animal Disease Centre.
34 The
results, published in 1994, showed that this source of scrapie agent, though
pathogenic for cattle, did not produce the same clinical signs of brain
lesions characteristic of BSE.

3.58 There are several possible reasons why the experiment was not performed
in the UK. It had been recommended by Sir Richard Southwood (Chairman of the
Working Party on Bovine Spongiform Encephalopathy) in his letter to the
Permanent Secretary of MAFF, Mr (now Sir) Derek Andrews, on 21 June 1988, 35
though it was not specifically recommended in the Working Party Report or
indeed in the Tyrrell Committee Report (details of the Southwood Working
Party and the Tyrell Committee can be found in vol. 4: The Southwood Working
Party, 1988-89 and vol. 11: Scientists after Southwood respectively). The
direct inoculation of scrapie into calves was given low priority, because of
its high cost and because it was known that it had already taken place in
the USA. 36 It was also felt that the results of such an experiment would be
hard to interpret. While a negative result would be informative, a positive
result would need to demonstrate that when scrapie was transmitted to
cattle, the disease which developed in cattle was the same as BSE. 37 Given
the large number of strains of scrapie and the possibility that BSE was one
of them, it would be necessary to transmit every scrapie strain to cattle
separately, to test the hypothesis properly. Such an experiment would be
expensive. Secondly, as measures to control the epidemic took hold, the need
for the experiment from the policy viewpoint was not considered so urgent.
It was felt that the results would be mainly of academic interest. 38

The Committee met on November 9, 2005, from 8:00am until 11:55am, Hershey Lodge and Convention Center, Hershey, Pennsylvania. The meeting was called to order by Dr. Jim Logan, chair, with vice chairman Dr. Joe D. Ross attending. There were 74 people in attendance.

The Scrapie Program Update was provided by Dr. Diane Sutton, National Scrapie Program Coordinator, United States Department of Agriculture (USDA), Animal and Plant Health Inspection Services (APHIS), Veterinary Services (VS). The complete text of the Status Report is included in these Proceedings.

Dr. Patricia Meinhardt, USDA-APHIS-VS-National Veterinary Services Laboratory (NVSL) gave the Update on Genotyping Labs and Discrepancies in Results. NVSL conducts investigations into discrepancies on genotype testing results associated with the Scrapie Eradication Program. It is the policy of the Program to conduct a second genotype test at a second laboratory on certain individual animals. Occasionally, there are discrepancies in those results. The NVSL conducts follow-up on these situations through additional testing on additional samples from the field and archive samples from the testing laboratories.

For the period of time from January 1, 2005, until October 15, 2005, there were 23 instances of discrepancies in results from 35 flocks. Of those 23 instances, 14 were caused by laboratory error (paperwork or sample mix-up), 3 results from field error, 5 were not completely resolved, and 1 originated from the use of a non-approved laboratory for the first test. As a result of inconsistencies, one laboratory’s certification was revoked by APHIS-VS.

snip…

Infected and Source Flocks

As of September 30, 2005, there were 105 scrapie infected and source flocks. There were a total of 165** new infected and source flocks reported for FY 2005. The total infected and source flocks that have been released in FY 2005 was 128. The ratio of infected and source flocks cleaned up or placed on clean up plans vs. new infected and source flocks discovered in FY 2005 was 1.03 : 1*. In addition 622 scrapie cases were confirmed and reported by the National Veterinary Services Laboratories (NVSL) in FY 2005, of which 130 were RSSS cases. Fifteen cases of scrapie in goats have been reported since 1990. The last goat case was reported in May 2005. Approximately 5,626 animals were indemnified comprised of 49% non-registered sheep, 45% registered sheep, 1.4% non-registered goats and 4.6% registered goats.

2003. It is a targeted slaughter surveillance program which is designed to identify infected flocks for clean-up. During FY 2005 collections increased by 32% overall and by 90% for black and mottled faced sheep improving overall program effectiveness and efficiency as demonstrated by the 26% decrease in percent positive black faced sheep compared to FY 2004. Samples have been collected from 62,864 sheep since April 1, 2003, of which results have been reported for 59,105 of which 209 were confirmed positive. During FY 2005, 33,137 samples were collected from 81 plants. There have been 130 NVSL confirmed positive cases (30 collected in FY 2004 and confirmed in FY 2005 and 100 collected and confirmed in FY 2005) in FY 2005. Face colors of these positives were 114 black, 14 mottled, 1 white and 1 unknown. The percent positive by face color is shown in the chart below.

As of October 04, 2005, 103,580 sheep and goat premises have been assigned identification numbers in the Scrapie National Generic Database. Official eartags have been issued to 73,807 of these premises.

*This number based on an adjusted 12 month interval to accommodate the 60 day period for setting up flock plans.

Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved September 12, 2005 (received for review March 21, 2005)

Scrapie in small ruminants belongs to transmissible spongiform encephalopathies (TSEs), or prion diseases, a family of fatal neurodegenerative disorders that affect humans and animals and can transmit within and between species by ingestion or inoculation. Conversion of the host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission and pathogenesis. The intensified surveillance of scrapie in the European Union, together with the improvement of PrPSc detection techniques, has led to the discovery of a growing number of so-called atypical scrapie cases. These include clinical Nor98 cases first identified in Norwegian sheep on the basis of unusual pathological and PrPSc molecular features and “cases” that produced discordant responses in the rapid tests currently applied to the large-scale random screening of slaughtered or fallen animals. Worryingly, a substantial proportion of such cases involved sheep with PrP genotypes known until now to confer natural resistance to conventional scrapie. Here we report that both Nor98 and discordant cases, including three sheep homozygous for the resistant PrPARR allele (A136R154R171), efficiently transmitted the disease to transgenic mice expressing ovine PrP, and that they shared unique biological and biochemical features upon propagation in mice. These observations support the view that a truly infectious TSE agent, unrecognized until recently, infects sheep and goat flocks and may have important implications in terms of scrapie control and public health.

Scrapie is a natural disease of sheep and goats. It is a slow
and inexorably progressive degenerative disorder of the nervous system
and it ia fatal. It is enzootic in the United Kingdom but not in all
countries.

The field problem has been reviewed by a MAFF working group
(ARC 35/77). It is difficult to assess the incidence in Britain for
a variety of reasons but the disease causes serious financial loss;
it is estimated that it cost Swaledale breeders alone $l.7 M during
the five years 1971-1975. A further inestimable loss arises from the
closure of certain export markets, in particular those of the United
States, to British sheep.

It is clear that scrapie in sheep is important commercially and
for that reason alone effective measures to control it should be
devised as quickly as possible.

Recently the question has again been brought up as to whether
scrapie is transmissible to man. This has followed reports that the
disease has been transmitted to primates. One particularly lurid
speculation (Gajdusek 1977) conjectures that the agents of scrapie,
kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of
mink are varieties of a single “virus”. The U.S. Department of
Agriculture concluded that it could “no longer justify or permit
scrapie-blood line and scrapie-exposed sheep and goats to be processed
for human or animal food at slaughter or rendering plants” (ARC 84/77)”
The problem is emphasised by the finding that some strains of scrapie
produce lesions identical to the once which characterise the human
dementias”

Whether true or not. the hypothesis that these agents might be
transmissible to man raises two considerations. First, the safety
of laboratory personnel requires prompt attention. Second, action
such as the “scorched meat” policy of USDA makes the solution of the
acrapie problem urgent if the sheep industry is not to suffer
grievously.

Like lambs to the slaughter
31 March 2001
Debora MacKenzie
Magazine issue 2284
What if you can catch old-fashioned CJD by eating meat from a sheep infected
with scrapie?
FOUR years ago, Terry Singeltary watched his mother die horribly from a
degenerative brain disease. Doctors told him it was Alzheimer’s, but
Singeltary was suspicious. The diagnosis didn’t fit her violent symptoms,
and he demanded an autopsy. It showed she had died of sporadic
Creutzfeldt-Jakob disease.

Most doctors believe that sCJD is caused by a prion protein deforming by
chance into a killer. But Singeltary thinks otherwise. He is one of a number
of campaigners who say that some sCJD, like the variant CJD related to BSE,
is caused by eating meat from infected animals. Their suspicions have
focused on sheep carrying scrapie, a BSE-like disease that is widespread in
flocks across Europe and North America.

Now scientists in France have stumbled across new evidence that adds weight
to the campaigners’ fears. To their complete surprise, the researchers found
that one strain of scrapie causes the same brain damage in …

There is substantial scientific evidence to support the notion that bovine
spongiform encephalopathy (BSE) has contaminated human beings, causing
variant Creutzfeldt-Jakob disease (vCJD). This disease has raised concerns
about the possibility of an iatrogenic secondary transmission to humans,
because the biological properties of the primate-adapted BSE agent are
unknown. We show that (i) BSE can be transmitted from primate to primate by
intravenous route in 25 months, and (ii) an iatrogenic transmission of vCJD
to humans could be readily recognized pathologically, whether it occurs by
the central or peripheral route. Strain typing in mice demonstrates that the
BSE agent adapts to macaques in the same way as it does to humans and
confirms that the BSE agent is responsible for vCJD not only in the United
Kingdom but also in France. The agent responsible for French iatrogenic
growth hormone-linked CJD taken as a control is very different from vCJD but
is similar to that found in one case of sporadic CJD and one sheep scrapie
isolate. These data will be key in identifying the origin of human cases of
prion disease, including accidental vCJD transmission, and could provide
bases for vCJD risk assessment.

5. Predicted population effects on free-ranging elk based on captive elk chronically exposed to the CWD prion.
Forty-three female elk calves were trapped at the National Elk Refuge and transported to Sybille in February 2002. Elk were housed in pens, assumed to be environmentally contaminated with the CWD prion. Elk will be held throughout their lifetimes. Elk dying will be examined and cause of death determined. From these data, it will should be possible to model free-ranging elk mortality and population dynamics under extreme circumstances of CWD prion exposure and transmission. As of December 2005 (46 months post capture), 11 of 43 elk have died due to CWD. This compares to 100% mortality in less than 25 months in elk orally inoculated with different dosages of the CWD prion.

Prions are transmissible proteinaceous agents of mammals that cause fatal
neurodegenerative diseases of the central nervous system (CNS). The presence
of infectivity in skeletal muscle of experimentally infected mice raised the
possibility that dietary exposure to prions might occur through meat
consumption (1). Chronic wasting disease (CWD), an enigmatic and contagious
prion disease of North American cervids, is of particular concern. The
emergence of CWD in an increasingly wide geographic area and the
interspecies transmission of bovine spongiform encephalopathy (BSE) to
humans as variant Creutzfeldt Jakob disease (vCJD) have raised concerns
about zoonotic transmission of CWD.

To test whether skeletal muscle of diseased cervids contained prion
infectivity, Tg(CerPrP)1536 mice (2) expressing cervid prion protein
(CerPrP), were inoculated intracerebrally with extracts prepared from the
semitendinosus/semimembranosus muscle group of CWD-affected mule deer or
from CWD-negative deer. The availability of CNS materials also afforded
direct comparisons of prion infectivity in skeletal muscle and brain. All
skeletal muscle extracts from CWD-affected deer induced progressive
neurological dysfunction in Tg(CerPrP)1536 mice with mean incubation times
ranging between 360 and ~490 d, whereas the incubation times of prions from
the CNS ranged from ~230 to 280 d (Table 1). For each inoculation group, the
diagnosis of prion disease was confirmed by the presence of PrPSc in the
brains of multiple infected Tg(CerPrP)1536 mice (see supporting online
material for examples). In contrast, skeletal muscle and brain material from
CWD-negative deer failed to induce disease in Tg(CerPrP)1536 mice (Table 1)
and PrPSc was not detected in the brains of sacrificed asymptomatic mice as
late as 523 d after inoculation (supporting online material).

Our results show that skeletal muscle as well as CNS tissue of deer with CWD
contains infectious prions. Similar analyses of skeletal muscle BSE-affected
cattle did not reveal high levels of prion infectivity (3). It will be
important to assess the cellular location of PrPSc in muscle. Notably, while
PrPSc has been detected in muscles of scrapie-affected sheep (4), previous
studies failed to detect PrPSc by immunohistochemical analysis of skeletal
muscle from deer with natural or experimental CWD (5, 6). Since the time of
disease onset is inversely proportional to prion dose (7), the longer
incubation times of prions from skeletal muscle extracts compared to matched
brain samples indicated that prion titers were lower in muscle than in CNS
where infectivity titers are known to reach high levels. Although possible
effects of CWD strains or strain mixtures on these incubation times cannot
be excluded, the variable 360 to ~490 d incubation times suggested a range
of prion titers in skeletal muscles of CWD-affected deer. Muscle prion
titers at the high end of the range produced the fastest incubation times
that were ~30% longer than the incubation times of prions from the CNS of
the same animal. Since all mice in each inoculation group developed disease,
prion titers in muscle samples producing the longest incubation times were
higher than the end point of the bioassay, defined as the infectious dose at
which half the inoculated mice develop disease. Studies are in progress to
accurately assess prion titers.

While the risk of exposure to CWD infectivity following consumption of
prions in muscle is mitigated by relatively inefficient prion transmission
via the oral route (8), these

results show that semitendinosus/semimembranosus muscle, which is likely to
be consumed by humans, is a significant source of prion infectivity. Humans
consuming or handling meat from CWD-infected deer are therefore at risk to
prion exposure.

9. This work was supported by grants from the U.S. Public Health Service
2RO1 NS040334-04 from the National Institute of Neurological Disorders and
Stroke and N01-AI-25491 from the National Institute of Allergy and
Infectious Diseases.

Isn’t there a possibility that the ban on cannibalism imposed by the Australians was not enforced properly, so that some of the Fore continued practicing the mortuary rituals?

I suppose anything’s possible, but I don’t know of any evidence to support that. Additionally, if that were the case, you’d expect to see cases in people born after the ban, and none have been reported to my knowledge.

>>>Re the main article: I don’t have access to the article itself, or most medical research at all at the moment, but I’m curious if the nvCJD incidence in Europe is rising or falling right now. From what I recall in the news, it was still rising in the late 1990s. They seem to be in the midst of the homozygote-portion of the epidemic right now, and the present trend should give us a hint at what part of the incidence over time curve we presently sit. From the kuru data, we would also anticipate a boomlet far into the future of heterozygotes, but it should be very much smaller and more diffuse than the homozygote boom, if it manifests at all.< <<

The early clinical, epidemiological, and anthropological study of kuru; the
recognition of its neuropathological, and then causal parallels to ovine
scrapie;20 and then crucially, the experimental transmission of the disease

J Whitfield led the field patrol team throughout the study and investigated
all suspect cases; E McKintosh provided assistance during this time. J Beck
and S Mead undertook the molecular genetic studies. J Collinge, M P Alpers,
E McKintosh, and D J Thomas did field neurological examinations. J Collinge
and M P Alpers supervised the study and drafted the manuscript. All authors
contributed to and approved the final version of the manuscript. ………

Summary
Background
Kuru provides the principal experience of epidemic human prion disease. Its
incidence has steadily fallen after the abrupt cessation of its route of
transmission (endocannibalism) in Papua New Guinea in the 1950s. The onset
of variant Creutzfeldt-Jakob disease (vCJD), and the unknown prevalence of
infection after the extensive dietary exposure to bovine spongiform
encephalopathy (BSE) prions in the UK, has led to renewed interest in kuru.
We investigated possible incubation periods, pathogenesis, and genetic
susceptibility factors in kuru patients in Papua New Guinea.

Methods
We strengthened active kuru surveillance in 1996 with an expanded field team
to investigate all suspected patients. Detailed histories of residence and
exposure to mortuary feasts were obtained together with serial neurological
examination, if possible.

Findings
We identified 11 patients with kuru from July, 1996, to June, 2004, all
living in the South Fore. All patients were born before the cessation of
cannibalism in the late 1950s. The minimum estimated incubation periods
ranged from 34 to 41 years. However, likely incubation periods in men ranged
from 39 to 56 years and could have been up to 7 years longer. PRNP analysis
showed that most patients with kuru were heterozygous at polymorphic codon
129, a genotype associated with extended incubation periods and resistance
to prion disease.

Interpretation
Incubation periods of infection with human prions can exceed 50 years. In
human infection with BSE prions, species-barrier effects, which are
characteristic of cross-species transmission, would be expected to further
increase the mean and range of incubation periods, compared with recycling
of prions within species. These data should inform attempts to model variant
CJD epidemiology.

Listen to The Lancet
This week’s audio summary discusses an Article entitled “Kuru in the 21st
century – an acquired human prion disease with very long incubation
periods”. Also covered is a Lecture assessing climate change and its impact
on health, and an Editorial about the roll-out of cervical cancer vaccines
worldwide. >>

vCJD, like kuru, is a prion disease
A disease linked to cannibalism has given clues about how long mad cow
disease (BSE) can lurk in the human body before it develops into vCJD.

A University College London team said it could take 50 years for vCJD, the
human form of the disease, to develop.

They studied Papua New Guineans with a related condition – kuru disease,
which is contracted through cannibalism.

In The Lancet, the team said people with a certain genetic make-up risked
long-term vCJD incubation.

By investigating kuru, the only known example of a major epidemic of a prion
disease, we will begin to narrow our present uncertainties about vCJD

The Lancet

Exposure to BSE (bovine spongiform encephalopathy) in the UK has been
widespread, although just 160 vCJD (variant Creutzfeldt-Jakob) patients have
been identified, leading scientists to investigate why more people have not
been affected so far.

Kuru disease, like vCJD, is a prion disease. Prions are mutated proteins.

It reached epidemic proportions in some Papua New Guinea communities early
in the 20th Century.

Eating dead relatives as a mark of respect and mourning was ritual practice
until it was banned in the 1950s.

In the study, 11 patients with kuru were identified between July 1996 to
June 2004, with the last one born in 1959.

Although it was not possible to know the exact date the patients contracted
kuru, the possible incubation periods ranged from 34 to 56 years.

Genetic differences

The researchers believe the incubation period for BSE prions in humans could
be even longer than that seen in kuru because infection between different
species typically takes longer to develop than one passed within the same
species.

Professor John Collinge, who led the study, said vCJD patients identified so
far “could represent a distinct genetic subpopulation with unusually short
incubation periods for BSE”.

He said a human BSE epidemic might have a number of phases, and added:
“Recent estimates of the size of the vCJD epidemic based on uniform genetic
susceptibility could be substantial underestimations.”

An editorial in the Lancet stated: “The eventual size of the vCJD epidemic
remains uncertain.

“The number of infected individuals is still unknown.

“By investigating kuru, the only known example of a major epidemic of a
prion disease, we will begin to narrow our present uncertainties about vCJD.

“Any belief that vCJD incidence has peaked and that we are now through the
worst of this sinister disease must now be treated with extreme scepticism.”

CASES ARE RISING OF THE SPORADIC STRAIN IN THE UK AND IN OTHER COUNTRIES, AS IN THE USA WHERE IT HAS TRIPLED OVER RECENT YEARS, AND THE MOST DISTURBING FACTOR, THERE ARE ”UNKNOWN” PHENOTYPES AND OR STRAINS I.E. ATYPICAL AS WITH THE LAST MAD COW IN TEXAS AND THE ONE IN ALABAMA, BOTH ATYPICAL TSE I.E. BASE HERE IS THE LATEST ON BASE CDC JUST PUT OUT, OF WHICH I BEEN TRYING TO WARN FOLKS FOR YEARS. …TSS

Subject: Transmission of New Bovine Prion to Mice
Date: July 6, 2006 at 1:18 pm PST
Transmission of

Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved December 23, 2003 (received for review September 9, 2003)

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are mammalian neurodegenerative disorders characterized by a posttranslational conversion and brain accumulation of an insoluble, protease-resistant isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). Human and animal TSE agents exist as different phenotypes that can be biochemically differentiated on the basis of the molecular mass of the protease-resistant PrPSc fragments and the degree of glycosylation. Epidemiological, molecular, and transmission studies strongly suggest that the single strain of agent responsible for bovine spongiform encephalopathy (BSE) has infected humans, causing variant Creutzfeldt-Jakob disease. The unprecedented biological properties of the BSE agent, which circumvents the so-called “species barrier” between cattle and humans and adapts to different mammalian species, has raised considerable concern for human health. To date, it is unknown whether more than one strain might be responsible for cattle TSE or whether the BSE agent undergoes phenotypic variation after natural transmission. Here we provide evidence of a second cattle TSE. The disorder was pathologically characterized by the presence of PrP-immunopositive amyloid plaques, as opposed to the lack of amyloid deposition in typical BSE cases, and by a different pattern of regional distribution and topology of brain PrPSc accumulation. In addition, Western blot analysis showed a PrPSc type with predominance of the low molecular mass glycoform and a protease-resistant fragment of lower molecular mass than BSE-PrPSc. Strikingly, the molecular signature of this previously undescribed bovine PrPSc was similar to that encountered in a distinct subtype of sporadic Creutzfeldt-Jakob disease.

Between FYs 2002 and 2004, FSIS condemned 680 cattle of all ages due to CNS
symptoms. About 357 of these could be classified as adult. We could validate
that ONLY 162 were tested for BSE (per APHIS records. …

snip…

WE interviewed officials at five laboratories that test for rabies. Those
officials CONFIRMED THEY ARE NOT REQUIRED TO SUBMIT RABIES-NEGATIVE SAMPLES
TO APHIS FOR BSE TESTING. A South Dakota laboratory official said they were
not aware they could submit rabies-negative samples to APHIS for BSE
testing. A laboratory official in another State said all rabies-negative
cases were not submitted to APHIS because BSE was ”NOT ON THEIR RADAR
SCREEN.” Officials from New York, Wisconsin, TEXAS, and Iowa advised they
would NOT submit samples from animals they consider too young. Four of the
five States contacted defined this age as 24 months; Wisconsin defined it as
30 months. TEXAS officials also advised that they do not always have
sufficient tissue remaining to submit a BSE sample. …

Bovine Spongiform Encephalopathy (BSE) is a prion
disease of cattle. Since 1986, when BSE was recognized,
over 180,000 cattle in the UK have developed the
disease, and approximately one to three million are
likely to have been infected with the BSE agent, most
of which were slaughtered for human consumption before
developing signs of the disease. The origin of the
first case of BSE is unknown, but the epidemic was
caused by the recycling of processed waste parts of
cattle, some of which were infected with the BSE agent
and given to other cattle in feed. Control measures
have resulted in the consistent decline of the epidemic
in the UK since 1992. Infected cattle and feed exported
from the UK have resulted in smaller epidemics in other
European countries, where control measures were applied
later.

Compelling evidence indicates that BSE can be
transmitted to humans through the consumption of prion
contaminated meat. BSE-infected individuals eventually
develop vCJD with an incubation time believed to be on
average 10 years. As of November 2004, three cases of
BSE have been reported in North America. One had been
imported to Canada from the UK, one was grown in
Canada, and one discovered in the USA but of Canadian
origin. There has been only one case of vCJD reported
in the USA, but the patient most likely acquired the
disease in the United Kingdom. If current control
measures intended to protect public and animal health
are well enforced, the cattle epidemic should be
largely under control and any remaining risk to humans
through beef consumption should be very small. (For
more details see Smith et al. British Medical Bulletin,
66: 185. 2003.)

Chronic Wasting Disease (CWD) is a prion disease of elk
and deer, both free range and in captivity. CWD is
endemic in areas of Colorado, Wyoming, and Nebraska,
but new foci of this disease have been detected in
Nebraska, South Dakota, New Mexico, Wisconsin,
Mississippi Kansas, Oklahoma, Minnesota, Montana, and
Canada. Since there are an estimated 22 million elk and
deer in the USA and a large number of hunters who
consume elk and deer meat, there is the possibility
that CWD can be transmitted from elk and deer to
humans. As of November 2004, the NPDPSC has examined 26
hunters with a suspected prion disease. However, all of
them appeared to have either typical sporadic or
familial forms of the disease. The NPDPSC coordinates
with the Centers for Disease Control and state health
departments to monitor cases from CWD-endemic areas.
Furthermore, it is doing experimental research on CWD
transmissibility using animal models. (For details see
Sigurdson et al. British Medical Bulletin. 66: 199.
2003 and Belay et al. Emerging Infectious Diseases.
10(6): 977. 2004.)

SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM
1997 TO 2004. SPORADIC CJD CASES TRIPLED, and that is
with a human TSE surveillance system that is terrible
flawed. in 1997 cases of the _reported_ cases of cjd
were at 54, to 163 _reported_ cases in 2004. see stats
here;

Objective:
The objective of this cooperative research project with Dr. Maria Caramelli
from the Italian BSE Reference Laboratory in Turin, Italy, is to conduct
comparative studies with the U.S. bovine spongiform encephalopathy (BSE)
isolate and the atypical BSE isolates identified in Italy. The studies will
cover the following areas: 1. Evaluation of present diagnostics tools used
in the U.S. for the detection of atypical BSE cases. 2. Molecular comparison
of the U.S. BSE isolate and other typical BSE isolates with atypical BSE
cases. 3. Studies on transmissibility and tissue distribution of atypical
BSE isolates in cattle and other species.

Approach:
This project will be done as a Specific Cooperative Agreement with the
Italian BSE Reference Laboratory, Istituto Zooprofilattico Sperimentale del
Piemonte, in Turin, Italy. It is essential for the U.S. BSE surveillance
program to analyze the effectiveness of the U.S diagnostic tools for
detection of atypical cases of BSE. Molecular comparisons of the U.S. BSE
isolate with atypical BSE isolates will provide further characterization of
the U.S. BSE isolate. Transmission studies are already underway using brain
homogenates from atypical BSE cases into mice, cattle and sheep. It will be
critical to see whether the atypical BSE isolates behave similarly to
typical BSE isolates in terms of transmissibility and disease pathogenesis.
If transmission occurs, tissue distribution comparisons will be made between
cattle infected with the atypical BSE isolate and the U.S. BSE isolate.
Differences in tissue distribution could require new regulations regarding
specific risk material (SRM) removal.

3.57 The experiment which might have determined whether BSE and scrapie were
caused by the same agent (ie, the feeding of natural scrapie to cattle) was
never undertaken in the UK. It was, however, performed in the USA in 1979,
when it was shown that cattle inoculated with the scrapie agent endemic in
the flock of Suffolk sheep at the United States Department of Agriculture in
Mission, Texas, developed a TSE quite unlike BSE. 32 The findings of the
initial transmission, though not of the clinical or neurohistological
examination, were communicated in October 1988 to Dr Watson, Director of the
CVL, following a visit by Dr Wrathall, one of the project leaders in the
Pathology Department of the CVL, to the United States Department of
Agriculture. 33 The results were not published at this point, since the
attempted transmission to mice from the experimental cow brain had been
inconclusive. The results of the clinical and histological differences
between scrapie-affected sheep and cattle were published in 1995. Similar
studies in which cattle were inoculated intracerebrally with scrapie inocula
derived from a number of scrapie-affected sheep of different breeds and from
different States, were carried out at the US National Animal Disease Centre.
34 The results, published in 1994, showed that this source of scrapie agent,
though pathogenic for cattle, did not produce the same clinical signs of
brain lesions characteristic of BSE.

The findings of the initial transmission, though not of the clinical or
neurohistological examination, were communicated in October 1988 to Dr
Watson, Director of the CVL, following a visit by Dr Wrathall, one of the
project leaders in the Pathology Department of the CVL, to the United States
Department of Agriculture. 33

The results were not published at this point, since the attempted
transmission to mice from the experimental cow brain had been inconclusive.
The results of the clinical and histological differences between
scrapie-affected sheep and cattle were published in 1995. Similar studies in
which cattle were inoculated intracerebrally with scrapie inocula derived
from a number of scrapie-affected sheep of different breeds and from
different States, were carried out at the US National Animal Disease Centre.
34 The
results, published in 1994, showed that this source of scrapie agent, though
pathogenic for cattle, did not produce the same clinical signs of brain
lesions characteristic of BSE.

3.58 There are several possible reasons why the experiment was not performed
in the UK. It had been recommended by Sir Richard Southwood (Chairman of the
Working Party on Bovine Spongiform Encephalopathy) in his letter to the
Permanent Secretary of MAFF, Mr (now Sir) Derek Andrews, on 21 June 1988, 35
though it was not specifically recommended in the Working Party Report or
indeed in the Tyrrell Committee Report (details of the Southwood Working
Party and the Tyrell Committee can be found in vol. 4: The Southwood Working
Party, 1988-89 and vol. 11: Scientists after Southwood respectively). The
direct inoculation of scrapie into calves was given low priority, because of
its high cost and because it was known that it had already taken place in
the USA. 36 It was also felt that the results of such an experiment would be
hard to interpret. While a negative result would be informative, a positive
result would need to demonstrate that when scrapie was transmitted to
cattle, the disease which developed in cattle was the same as BSE. 37 Given
the large number of strains of scrapie and the possibility that BSE was one
of them, it would be necessary to transmit every scrapie strain to cattle
separately, to test the hypothesis properly. Such an experiment would be
expensive. Secondly, as measures to control the epidemic took hold, the need
for the experiment from the policy viewpoint was not considered so urgent.
It was felt that the results would be mainly of academic interest. 38

The Committee met on November 9, 2005, from 8:00am until 11:55am, Hershey
Lodge and Convention Center, Hershey, Pennsylvania. The meeting was called
to order by Dr. Jim Logan, chair, with vice chairman Dr. Joe D. Ross
attending. There were 74 people in attendance.

The Scrapie Program Update was provided by Dr. Diane Sutton, National
Scrapie Program Coordinator, United States Department of Agriculture (USDA),
Animal and Plant Health Inspection Services (APHIS), Veterinary Services
(VS). The complete text of the Status Report is included in these
Proceedings.

Dr. Patricia Meinhardt, USDA-APHIS-VS-National Veterinary Services
Laboratory (NVSL) gave the Update on Genotyping Labs and Discrepancies in
Results. NVSL conducts investigations into discrepancies on genotype testing
results associated with the Scrapie Eradication Program. It is the policy of
the Program to conduct a second genotype test at a second laboratory on
certain individual animals. Occasionally, there are discrepancies in those
results. The NVSL conducts follow-up on these situations through additional
testing on additional samples from the field and archive samples from the
testing laboratories.

For the period of time from January 1, 2005, until October 15, 2005, there
were 23 instances of discrepancies in results from 35 flocks. Of those 23
instances, 14 were caused by laboratory error (paperwork or sample mix-up),
3 results from field error, 5 were not completely resolved, and 1 originated
from the use of a non-approved laboratory for the first test. As a result of
inconsistencies, one laboratory’s certification was revoked by APHIS-VS.

snip…

Infected and Source Flocks

As of September 30, 2005, there were 105 scrapie infected and source flocks.
There were a total of 165** new infected and source flocks reported for FY
2005. The total infected and source flocks that have been released in FY
2005 was 128. The ratio of infected and source flocks cleaned up or placed
on clean up plans vs. new infected and source flocks discovered in FY 2005
was 1.03 : 1*. In addition 622 scrapie cases were confirmed and reported by
the National Veterinary Services Laboratories (NVSL) in FY 2005, of which
130 were RSSS cases. Fifteen cases of scrapie in goats have been reported
since 1990. The last goat case was reported in May 2005. Approximately 5,626
animals were indemnified comprised of 49% non-registered sheep, 45%
registered sheep, 1.4% non-registered goats and 4.6% registered goats.

2003. It is a targeted slaughter surveillance program which is designed to
identify infected flocks for clean-up. During FY 2005 collections increased
by 32% overall and by 90% for black and mottled faced sheep improving
overall program effectiveness and efficiency as demonstrated by the 26%
decrease in percent positive black faced sheep compared to FY 2004. Samples
have been collected from 62,864 sheep since April 1, 2003, of which results
have been reported for 59,105 of which 209 were confirmed positive. During
FY 2005, 33,137 samples were collected from 81 plants. There have been 130
NVSL confirmed positive cases (30 collected in FY 2004 and confirmed in FY
2005 and 100 collected and confirmed in FY 2005) in FY 2005. Face colors of
these positives were 114 black, 14 mottled, 1 white and 1 unknown. The
percent positive by face color is shown in the chart below.

As of October 04, 2005, 103,580 sheep and goat premises have been assigned
identification numbers in the Scrapie National Generic Database. Official
eartags have been issued to 73,807 of these premises.

*This number based on an adjusted 12 month interval to accommodate the 60
day period for setting up flock plans.

Edited by Stanley B. Prusiner, University of California, San Francisco, CA,
and approved September 12, 2005 (received for review March 21, 2005)

Scrapie in small ruminants belongs to transmissible spongiform
encephalopathies (TSEs), or prion diseases, a family of fatal
neurodegenerative disorders that affect humans and animals and can transmit
within and between species by ingestion or inoculation. Conversion of the
host-encoded prion protein (PrP), normal cellular PrP (PrPc), into a
misfolded form, abnormal PrP (PrPSc), plays a key role in TSE transmission
and pathogenesis. The intensified surveillance of scrapie in the European
Union, together with the improvement of PrPSc detection techniques, has led
to the discovery of a growing number of so-called atypical scrapie cases.
These include clinical Nor98 cases first identified in Norwegian sheep on
the basis of unusual pathological and PrPSc molecular features and “cases”
that produced discordant responses in the rapid tests currently applied to
the large-scale random screening of slaughtered or fallen animals.
Worryingly, a substantial proportion of such cases involved sheep with PrP
genotypes known until now to confer natural resistance to conventional
scrapie. Here we report that both Nor98 and discordant cases, including
three sheep homozygous for the resistant PrPARR allele (A136R154R171),
efficiently transmitted the disease to transgenic mice expressing ovine PrP,
and that they shared unique biological and biochemical features upon
propagation in mice. These observations support the view that a truly
infectious TSE agent, unrecognized until recently, infects sheep and goat
flocks and may have important implications in terms of scrapie control and
public health.

Scrapie is a natural disease of sheep and goats. It is a slow
and inexorably progressive degenerative disorder of the nervous system
and it ia fatal. It is enzootic in the United Kingdom but not in all
countries.

The field problem has been reviewed by a MAFF working group
(ARC 35/77). It is difficult to assess the incidence in Britain for
a variety of reasons but the disease causes serious financial loss;
it is estimated that it cost Swaledale breeders alone $l.7 M during
the five years 1971-1975. A further inestimable loss arises from the
closure of certain export markets, in particular those of the United
States, to British sheep.

It is clear that scrapie in sheep is important commercially and
for that reason alone effective measures to control it should be
devised as quickly as possible.

Recently the question has again been brought up as to whether
scrapie is transmissible to man. This has followed reports that the
disease has been transmitted to primates. One particularly lurid
speculation (Gajdusek 1977) conjectures that the agents of scrapie,
kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of
mink are varieties of a single “virus”. The U.S. Department of
Agriculture concluded that it could “no longer justify or permit
scrapie-blood line and scrapie-exposed sheep and goats to be processed
for human or animal food at slaughter or rendering plants” (ARC 84/77)”
The problem is emphasised by the finding that some strains of scrapie
produce lesions identical to the once which characterise the human
dementias”

Whether true or not. the hypothesis that these agents might be
transmissible to man raises two considerations. First, the safety
of laboratory personnel requires prompt attention. Second, action
such as the “scorched meat” policy of USDA makes the solution of the
acrapie problem urgent if the sheep industry is not to suffer
grievously.